Design of new selective inhibitors of cyclooxygenase-2 by dynamic assemblyof molecular building blocks

A method of dynamically assembling molecular building blocks - DycoBlock - has been proposed and tested by Liu et al. [1]. This method is based on mul tiple-copy stochastic dynamics simulation in the presence of a receptor mol ecule. In this method, a novel algorithm was used to dynamically assemble t he molecular building blocks to form candidate compounds. Currently, some n ew improvements have been incorporated into DycoBlock to make it more effic ient. In the new version of DycoBlock, the binding energy and solvent acces sible surface area (SASA) can be used to screen the resulting compounds. A simple clustering algorithm based on molecular similarity was developed and used to classify the remaining compounds. The revised DycoBlock was tested by breaking SC-558 - a selective inhibitor of cyclooxygenase-2 (COX-2) - i nto building blocks and reassembling them in the active site of the enzyme. The accuracy of recovery grew to 58.8% while it was only 16.7% in the prev ious version. Then, thirty-three kinds of molecular building blocks were us ed in the design of novel inhibitors and the investigation of diversity. As a result, a total of 1441 compounds was generated with high diversity. Aft er the first screening procedure, there remained 864 reasonable compounds. The results from clustering indicate that the structural motifs in the diar ylheterocycle class of COX-2-selective inhibitors [2] have been generated u sing the revised DycoBlock, and their binding modes were investigated.